A randomized adaptive phase II/III study of buparlisib, a pan-class I PI3K inhibitor, combined with paclitaxel for the treatment of HER2- advanced breast cancer (BELLE-4).

Background: Phosphatidylinositol 3-kinase (PI3K) pathway activation in preclinical models of breast cancer is associated with tumor growth and resistance to anticancer therapies, including paclitaxel. Effects of the pan-Class I PI3K inhibitor buparlisib (BKM120) appear synergistic with paclitaxel in preclinical and clinical models. Patients and methods: BELLE-4 was a 1:1 randomized, double-blind, placebo-controlled, adaptive phase II/III study investigating the combination of buparlisib or placebo with paclitaxel in women with human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer with no prior chemotherapy for advanced disease. Patients were stratified by PI3K pathway activation and hormone receptor status. The primary endpoint was progression-free survival (PFS) in the full and PI3K pathway-activated populations. An adaptive interim analysis was planned following the phase II part of the study, after ≥125 PFS events had occurred in the full population, to decide whether the study would enter phase III (in the full or PI3K pathway-activated population) or be stopped for futility. Results: As of August 2014, 416 patients were randomized to receive buparlisib (207) or placebo (209) with paclitaxel. At adaptive interim analysis, there was no improvement in PFS with buparlisib versus placebo in the full (median PFS 8.0 versus 9.2 months, hazard ratio [HR] 1.18), or PI3K pathway-activated population (median PFS 9.1 versus 9.2 months, HR 1.17). The study met protocol-specified criteria for futility in both populations, and phase III was not initiated. Median duration of study treatment exposure was 3.5 months in the buparlisib arm versus 4.6 months in the placebo arm. The most frequent adverse events with buparlisib plus paclitaxel (≥40% of patients) were diarrhea, alopecia, rash, nausea, and hyperglycemia. Conclusions: Addition of buparlisib to paclitaxel did not improve PFS in the full or PI3K pathway-activated study population. Consequently, the trial was stopped for futility at the end of phase II.

Chaos control via feeding switching in an omnivory system.

Tanabe and Namba (Ecology, 86, 3411-3414) studied a three species Lotka-Volterra model with omnivory and explored that omnivory can create chaos. It is well documented that predator switching is a similar biological phenomenon to omnivory and likely to occur simultaneously. In the present paper, the tri-trophic Lotka-Volterra food web model with omnivory and predator switching is re-investigated. We observe that if we incorporate predator switching in the system and the intensity of predator switching increases above a threshold value, then the system will be stable from chaotic dynamics. To study the global dynamics of the system extensive numerical simulations are performed. Our analytical and numerical results suggest that predator switching mechanism enhances the stability and the persistence of a food chain system.

Analysis of a predator-prey system with predator switching.

In this paper, we consider an interaction of prey and predator species where prey species have the ability of group defence. Thresholds, equilibria and stabilities are determined for the system of ordinary differential equations. Taking carrying capacity as a bifurcation parameter, it is shown that a Hopf bifurcation can occur implying that if the carrying capacity is made sufficiently large by enrichment of the environment, the model predicts the eventual extinction of the predator providing strong support for the so-called 'paradox of enrichment'.

A study of prey-predator relations for mammals.

In this paper, we present a prey-predator nonlinear model for mammals, consisting of large- and small-size prey species with group defence, in a partially protected habitat. If the prey size is small, then it is more prone to the predator at higher densities. Conversely, large prey size at higher densities tend to develop group defence. Therefore, the predator will be attracted towards that area where prey are less in number. A new physical constant has been introduced into the radiation-type condition on that part of the boundary where interaction between prey and predator takes place. This constant allows us to efficiently model group defence capabilities of the herds and its numerical values have to be determined for different pairs of prey-predator species from field observations. A way of measuring the constants involved in the model is suggested. Numerical results are provided and thoroughly discussed for a habitat of circular shape. The obtained results show that in the region away from the protected area, the density of large-size prey species is higher than that of small-size prey species, a fact that is in accordance with observations.

The stability of internal equilibria in predator-prey models with breeding suppression.

We present two models that represent the suppression of breeding by prey in response to short-term increases in predation pressure. For both of these models, we have been able to produce analytic conditions for the local stability of the interior steady state, in terms of the values of combinations of these parameters. Although our models are as simple as possible to capture the effect of breeding suppression, the expressions for local stability, even in their simplest form, are complex. Thus, we come to the important conclusion that there is no simple and general rule for the effect of the behaviours described here (anti-predatory breeding suppression and prey switching by predators) on the stability of population dynamics. Rather, effects will be system specific. However, we hope that the results and methodological framework outlined here will provide a useful tool for others to investigate the consequences for particular real systems.

Effect of naproxen on the pharmacokinetic parameters of rifampicin.

The effect of naproxen (500 mg) on the pharmacokinetics of rifampicin (450 mg) was evaluated in healthy human subjects (n = 10). Subjects participated in a two way crossover trial, the first dosing condition was rifampicin alone (control), and the second dosing condition was naproxen with rifampicin. The concentrations of rifampicin from the serum samples were determined by HPLC. The pharmacokinetic parameters indicated a significant (P < 0.05) increase in elimination rate constant (Ke), clearance (Cl), volume of distribution (Vd), while significant decrease in the mean residence time (MRT), and area under the concentration-time curve (AUC). Insignificant increase and decrease in absorption rate constant (Ka), and elimination half-life (t1/2), time for maximum concentration (Tmax), maximum drug concentration (Cmax) respectively was observed.

Hopf bifurcation in epidemic models with a time delay in vaccination.

Two SIR models for the spread of infectious diseases which were originally suggested by Greenhalgh & Das (1995, Theor. Popul. Biol. 47, 129-179; 1995, Mathematical Population Dynamics: Analysis of Heterogeneity, pp. 79-101, Winnipeg: Wuerz Publishing) are considered but with a time delay in the vaccination term. This reflects the fact that real vaccines do not immediately confer permanent immunity. The population is divided into susceptible, infectious, and immune classes. The contact rate is constant in model I but it depends on the population size in model II. The death rate depends on the population size in both models. There is an additional mortality due to the disease, and susceptibles are vaccinated and may become permanently immune after a lapse of some time. Using the time delay as a bifurcation parameter, necessary and sufficient conditions for Hopf bifurcation to occur are derived. Numerical results indicate that that for diseases in human populations Hopf bifurcation is unlikely to occur at realistic parameter values if the death rate is a concave function of the population size.

Pharmacokinetic study about interaction of Naproxen and Isoniazid.

Effect of Naproxen (500 mg) was studied on the pharmacokinetic characteristics of Isoniazid (300 mg) in ten healthy human volunteers in a complete crossover design. A high performance liquid chromatography (HPLC) method was used to analyze serum drug concentrations. Naproxen caused a highly significant (P<0.001) increase in AUC, significant (P<0.05) increase in elimination half life (t(1/2)) and time for the maximum drug concentration (tmax) while significant (P<0.05) decrease in elimination rate constant (Kc). Insignificant decrease and increase was observed in absorption rate constant (Ka) and maximum drug concentration (Cmax) respectively.